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  • cgrp br Introduction Endothelial progenitor cells EPCs prese

    2024-05-15


    Introduction Endothelial progenitor cells (EPCs) present a class of blood cells with an ability to form new blood vessels relying on pre-existing vessels, which contribute to postnatal angiogenesis [1], [2]. A wide range of studies have demonstrated that EPCs play a critical role in angiogenesis [3], [4], [5]. In vitro, these cells form tube-like structures, and resemble vasculature in the presence of fibronectin [6], [7]. In vivo, infusion of human EPCs into ischemic limbs in mice can form new vessels, which increase the rates of blood flow recovery and capillary density [8], [9]. In addition, infusion of human CD133+CD34+VEGF2R+ EPC cells can be monitored in newly formed cgrp in a rat model with myocardial infarction [10]. Although the important role of EPCs in angiogenesis has been reported in multiple studies, the underlying mechanism is not well elucidated. MicroRNAs (miRNAs) represent a large class of small endogenous non-coding RNAs with 19–24 nucleotides in length, which repress target mRNA translation or induce mRNA degradation at the post-transcriptional level [11]. MiRNAs play a pivotal role in a wide range of physiological and pathological processes, including cell growth, apoptosis, development and differentiation, tumor initiation and progression, inflammation and angiogenesis [11]. MiR-503, an intragenic miRNA located on the chromosomal location Xq26.3, was first identified in human retinoblastoma tissues [12]. Moreover, the expression of miR-503 has been found to be elevated in parathyroid carcinomas and adrenocortical tumors [13], [14]. Along with macrophage differentiation, miR-503 induces cell cycle delay in G1 by targeting multiple cell cycle regulators [15]. In human umbilical vein epithelial cells and human microvascular epithelial cells, increased expression of miR-503 results in G1 arrest, reduces cellular growth and migration, suggesting an anti-angiogenic function of this miRNA [16], [17]. In bone marrow-derived mesenchymal stem cells (MSCs), Nie et al. have identified 57 miRNAs that are upregulated in MSCs with exposure to hypoxia for 6 h including miR-503, while down-regulation of miR-503 aggravates the apoptosis of MSCs [18]. However, the role of miR-503 in hypoxia-induced endothelial progenitor cells remains unclear. Hypoxia is a condition in which the body or a cell is deprived of adequate oxygen supply at the tissue level and associated with a wide range of physiological and pathological events including organ development, cardiovascular disorders, inflammation, tumorigenesis and ischemic diseases [19], [20], [21]. Hypoxia often leads to the restoration of oxygen homeostasis by the activation of angiogenesis [22]. Understanding the cellular pathways underlying angiogenesis induced by hypoxia is of great importance in the development of novel treatments for ischemic diseases. Although the pathways of angiogenesis have been extensively studied, the role of miRNAs in this process has not been well elucidated. As an endogenous ligand of the G protein-coupled receptor APJ, Apelin is mainly expressed in the brain and peripheral tissues. A growing body of evidence indicates that Apelin and APJ play critical roles in a broad range of pathological processes including acute ischemic stroke. Recently, accumulating attention has been focused on the important role of the Apelin/APJ system in vascular pathophysiology [23], [24], [25]. For instance, intranasal delivery of Apelin promotes angiogenesis in mice with ischemic stroke [26]. Furthermore, the Apelin/APJ system participates in physiological vascular development in collaboration with VEGF [27]. However, the precise role of the Apelin/APJ system in pathological angiogenesis is not well defined.
    Materials and methods
    Results
    Discussion It is believed that elucidating the molecular mechanisms underlying endothelial angiogenesis during hypoxia is beneficial for discovering novel treatments for ischemic diseases [22]. Although the cellular pathways of angiogenesis of EPCs have been extensively studied [19], [20], [21], the functions of miRNAs in EPC angiogenesis remain to be well defined. In this study, we found that the expression of miR-503 was downregulated in hypoxia-treated EPCs. Functionally, ectopic expression of miR-503 drastically suppressed cell proliferation, cell cycle progression, transwell migration and capillary-like tube formation in EPCs. Importantly, a mechanistic investigation revealed that miR-503 suppressed Apelin expression in EPCs. In addition, re-expression of Apelin promoted cellular growth, migration and angiogenesis in EPCs, which mimicking the effect of hypoxia on EPCs. Four major conclusions can be drawn from the findings of this study: (1) Hypoxia induces cell proliferation, migration and angiogenesis; (2) Suppression of miR-503 facilitates cell growth, migration and capillary-like tube formation in EPCs induced by hypoxia; (3) Apelin is a direct target of miR-503 in EPCs; (4) Increased expression of Apelin can mimicking the biological behaviors of EPCs under hypoxia. In conclusion, the cgrp miR-503/Apelin axis may be of importance in hypoxia-induced endothelial angiogenesis (Fig. 5).